1. Field of the Invention
The present invention is directed to novel progesterone derivatives, as well as to pharmaceutical compositions thereof, and methods of treatment using the derivatives. More particularly, the invention relates to C7-substituted derivatives of the pregnene series.
2. Related Art
Breast cancer is the most common cancer among women living in Western societies, with almost 11% of all women living to age 80 developing the disease (Miller & Bulbrook, Int. J. Cancer 37:173-177 (1986)). Despite being an initially responsive disease (Henderson & Shapiro, "Adjuvant chemotherapy: an overview," in Medical Management of Breast Cancer, Powles & Smith, eds., Dunitz, Lindon (1991), pp. 197-215), most cytotoxic drug-responsive breast tumors, either spontaneously or following the selective pressure of systemic therapies, acquire a phenotype of multiple metastatic lesions that are resistant to all endocrine and cytotoxic therapies (Clarke, R. et al., Ann. Oncol. 1:401-407 (1990); Clarke, R. et al., Breast Cancer Res. Treat. 24:227-239 (1993); Clarke & Leonessa, "Cytotoxic drugs and hormones in breast cancer: interactions at the cellular level," in Drug and Hormonal Resistance in Breast Cancer: Cellular and Molecular Mechanisms, Dickson & Lippman, eds., Ellis Harwood, Chichester, UK (1994), pp. 407-432; Leonessa, F. et al., Acta Oncol. 31:115-123 (1991)). Since this is the major cause of death in breast cancer patients, the development of novel agents for drug-resistant breast tumors is critical.
The precise genes that confer a multidrug-resistance phenotype in breast cancer are unknown, but there are several strong single-gene candidates. These include the PGP (P-glycoprotein) product of the MDR1 gene, the multidrug-resistance-associated protein (MRP), and the altered expression of detoxification (e.g., superoxide dismutases, glutathione transferases), stress (e.g., heat-shock proteins), and other genes (e.g., topoisomerases). The precise contribution of each potential multidrug-resistance mechanism is unclear, and it is likely that more than one mechanism can operate either within the same tumor cell subpopulation and/or within different subpopulations of the same tumor.
An important resistance mechanism, and one which is the subject of the present application, is PGP-mediated resistance, a critical component of the multidrug-resistance phenotype in breast cancer when its expression is detected in tumors.
Most studies readily detect MDR1/PGP expression in breast tumors. A meta-analysis of all the published reports of MDR1/PGP expression in human breast cancers was conducted from the literature (described herein). This approach provided the ability to combine large numbers of individual patients into one study. The data from the analysis indicate that regardless of the technique applied, there is a reproducible expression of detectable levels of PGP in 25% or more of all untreated breast tumors. This value increases to an incidence of 50% of MDR1/PGP-positive tumors in treated patients (p&lt;0.0001). Supporting preliminary evidence from two clinical studies that have addressed survival indicate reduced disease/progression-free survival in patients with PGP-positive breast cancers (Botti, G. et al., Tumori 79:214-218 (1993); Vernelle, P. et al., J. Natl. Cancer Inst. 83:111-116 (1991)). These data support a functional role for PGP in breast cancer. Thus, strategies to reverse PGP resistance are clearly needed.
Many of the more widely used drugs in breast cancer treatment, including the VINCA alkaloids, e.g., Vinblastine, and the anthrocycline antibiotics, e.g., Adriamycin, are substrates for PGP. The taxanes, which includes taxol, also exhibit significant activity in breast cancer and RPGP substrates (Gottesman, M. M., Cancer Res. 53:747-754 (1993)). Since PGP expression occurs in a high percentage of treated patients, there is a clear rationale for assuming that this expression can contribute to clinical resistance in these tumors.